Thyroxine (T4) - Synthesis and Metabolism

1. Regulation of Thyroid Hormone Production (HPT Axis)

• Hypothalamus releases TRH (thyrotropin-releasing hormone)
• TRH stimulates the anterior pituitary to secrete TSH (thyroid-stimulating hormone, a 31-kDa glycoprotein with α and β subunits)
• TSH binds its receptor (TSH-R, a 7-transmembrane GPCR) on follicular cells, activating adenylyl cyclase → ↑cAMP, driving hormone synthesis and secretion
• High circulating T4/T3 feeds back to suppress TRH and TSH, primarily via thyroid hormone receptor TRβ2

2. Thyroid Hormone Synthesis - Step by Step

Step 1 - Iodide Uptake (Trapping)

• Dietary iodine (minimum ~100 µg/day for adults) is absorbed and circulates as iodide (I-)
• Iodide is actively transported from blood into the follicular cell across the basolateral membrane by the sodium-iodide symporter (NIS) - an energy-dependent co-transporter driven by the Na+/K+ ATPase gradient
• The intracellular iodide concentration is many times higher than serum
• NIS is also expressed (at low levels) in salivary glands, lactating breast, and placenta; this selective expression is exploited for radioiodine scanning and therapy
• Iodide then moves toward the apical border and exits into the colloid via pendrin (an apical iodide transporter; pendrin mutation causes Pendred syndrome - goiter + sensorineural deafness)

Step 2 - Oxidation of Iodide

• In the colloid, iodide (I-) is oxidized to I₂ (reactive iodine) by thyroid peroxidase (TPO) using H₂O₂ as the oxidant
• H₂O₂ is generated by NADPH oxidases (DUOX1/DUOX2) at the apical membrane

Step 3 - Organification (Iodination of Thyroglobulin)

• TPO catalyzes the iodination of tyrosine residues on Tg within the colloid
• A single iodine on tyrosine → monoiodotyrosine (MIT)
• Two iodines on tyrosine → diiodotyrosine (DIT)
• This entire process is called organification of iodine

Step 4 - Coupling Reaction

• TPO also catalyzes the coupling of iodotyrosyl residues still on the Tg backbone:
  • DIT + DIT → T4 (tetraiodothyronine / thyroxine) - contains 4 iodine atoms
  • DIT + MIT → T3 (triiodothyronine) - contains 3 iodine atoms
• The coupling forms an ether linkage between the residues
• The thyroid secretes T4 in ~15-fold excess over T3

Step 5 - Reuptake and Proteolysis

• When stimulated by TSH, follicular cells endocytose Tg from the colloid
• Lysosomal proteases cleave Tg, releasing free T4, T3, MIT, and DIT
• MIT and DIT are deiodinated within the cell by iodotyrosine deiodinase (DEHAL1), recycling iodine
• Free T4 and T3 are secreted into the bloodstream

Key enzymes: NIS (iodide uptake), TPO (oxidation, organification, coupling), DUOX2 (H₂O₂ generation), pendrin (apical iodide efflux)

Wolff-Chaikoff effect: Excess iodide transiently inhibits organification. The normal thyroid "escapes" this effect; autoimmune glands may not escape, leading to hypothyroidism with iodide loading.

3. Transport in Blood

• ~99.98% of T4 and ~99.7% of T3 are protein-bound
• Only the free (unbound) fractions are biologically active
• T4 serum half-life: 7 days | T3 serum half-life: 2 days
• Total T4: ~8 µg/dL | Total T3: ~0.14 µg/dL

4. Peripheral Metabolism - Deiodination

Three Deiodinase Enzymes

• ~80% of circulating T3 comes from peripheral T4 → T3 conversion (only 20% secreted directly from thyroid)
• D2 is particularly important for brain and pituitary T3 supply; hypothyroidism upregulates D2 to protect these tissues
• Sick euthyroid / low T3 syndrome: D3 activation in illness shifts deiodination toward rT3, lowering active T3

Cellular Action

5. Other Metabolic Pathways

Conjugation (Hepatic and Renal)

• T4 and T3 undergo sulfation and glucuronidation in the liver and kidney, increasing water solubility
• Glucuronidated forms are excreted in bile; they may be deconjugated by gut bacteria and reabsorbed (enterohepatic circulation) - ~20% of T4 is excreted in feces
• Sulfated thyroid hormones are deiodinated and excreted in urine or feces

Decarboxylation / Thyronamines

• Iodothyronines can be further decarboxylated to thyronamines (biologically active metabolites)
• 3,5-T2 ("hot" hormone) - increases thermogenesis
• 3T1 ("cold" hormone) - decreases thermogenesis
• These nonclassical thyroid hormones are present at low plasma concentrations but are now recognized as having real physiologic effects

6. Nuclear Mechanism of Action

• Genomic actions: T3 binds nuclear thyroid hormone receptors (TRα, TRβ), which bind as monomers, homodimers, or heterodimers with retinoid X receptor (RXR) to thyroid response elements (TREs) in gene promoters → transcription of target genes
  • TRα: abundant in brain, heart, muscle, kidney
  • TRβ: high in pituitary and liver; TRβ2 mediates TSH negative feedback
• Nongenomic actions: T4 has higher affinity for cell-surface integrin αvβ3; rapid signaling via PI3K and cAMP kinase pathways (transcription-independent); direct mitochondrial effects increasing ATP production and oxygen consumption

Summary Table - Key Steps